Hooper Rebuttable

In April 2006 the British Medical Journal published the results of a Cochrane review of the risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer, by Lee Hooper and colleagues (BMJ. 2006;332:752-760).  In view of the fact that this review might have a bearing on ISSFAL's 2004 recommendation on polyunsaturated fatty acid intake, the Executive Committee of ISSFAL asked a panel of experts for their view on the Hooper  publication, and in particular on whether ISSFAL needed to review its recommendation in the light of the conclusions drawn by Hooper et al.

The panel comprised Clemens von Schacky, from the University of Munich,  in Germany; William S Harris, Sanford School of  Medicine, University of South Dakota , South Dakota , USA; Dariush Mozaffarian, Harvard Medical School ,Boston ,USA; and Penny M. Kris-Etherton,  The Pennslyvania State University, University Park, Pennsylvania,USA.

The response from the panel of experts is published below:
        A Cochrane meta-analysis has been published in the British Medical Journal, which came to the conclusion that “long chain and shorter chain omega 3 fats do not have a clear effect on total mortality, combined cardiovascular events, or cancer” 1. With respect to the former two endpoints, we disagree.
       The null conclusion of the Cochrane report rests entirely upon inclusion of one trial, DART 2 2. This was a randomized dietary trial with clinical endpoints testing the effects on total mortality of either giving advice to eat fish or providing fish oil capsules to men with angina. Surprisingly, while total mortality was not statistically different in the two groups, there was less sudden death in the control group than in the intervention group. Upon exclusion of DART 2 from the meta-analysis, the overall decrease in relative risk with omega-3 consumption became similar to that reported in a previous meta-analysis by Bucher et al: 0.83 (95% confidence interval, 0.75 to 0.91) 3 . 
        According to a number of criteria, the results of DART 2 have the characteristics of an outlier, as reflected in the Hooper paper by a positive test for heterogeneity which disappeared after removing DART 2 from the analysis.  DART 2 was an open-label, dietary advice trial designed similarly to DART 1 4 , only in men being treated for stable angina.  Although reasonably well-designed, it was seriously under-funded and thus not properly conducted or reported. For example, only a rudimentary set of baseline parameters is presented for all participants, while the rest of the data refer to small subgroups at a subset of time points. Compliance by analysis of blood fatty acid levels was checked in only 2% of the cohort and only at 6 months. Neither long-term compliance with the advice nor how concomitant medications and health behaviours may have changed are known. The authors offered several possible explanations for their admittedly aberrant findings, but none were particularly satisfying to them or to us. Taken together, the results were generated with inadequate methodology, and therefore, trying to make sense of the trial’s results is doomed to fail. For Hooper et al. to allow this one, highly suspect study to sway their conclusions reflects, in our view, poor judgement.   
        Even as it stands, the Cochrane analysis suggests a 16 – 17 % reduction in total mortality by ingestion of omega-3 fatty acids, an effect size that is even larger than that of statins 5 . That the confidence intervals overlap 1.0 indicates that further studies were needed to improve precision of the estimate, not that the estimate is wrong. A number of large omega-3 and CHD studies (both epidemiological and interventional) are currently underway (e.g., 6 ), and these will provide a much clearer picture of the extent to which cardiovascular morbidity and mortality may be reduced by omega-3 fatty acids. 
Other concerns about the Cochrane analysis include: 
  Omission of biomarker-based studies. Biomarkers, like serum, whole blood or red cell eicosapentaenoic acid and docosahexaenoic acid (e.g. the omega-3 index) or like adipose tissue fatty acids, better reflect dietary intakes of these FA than a diet questionnaire. It is well-known that fish vary widely in omega-3 fatty acid content across species, living conditions and a host of other factors. In the Cochrane analysis, however, biomarker-based epidemiological studies were (we believe inappropriately) excluded.
   Omission of relevant cohort studies. Only 3 cohort studies were included, while a number of other cohort studies were not because they “assessed only fish intake,” which the authors said, “is not clearly related to omega-3 intake”. Omega-3 intake is clearly (but not     perfectly) related to fish intake, so to exclude these studies seriously weakens the study’s conclusions. 
Inclusion of a study of questionable scientific integrity. The British Medical Journal has published a long article shedding serious doubt on  the credibility of the work of RB Singh 7 . Nevertheless, a study from this author was included.
   Inclusion of studies not designed to detect effects on mortality, cardiovascular disease, and cancer.
Contradiction in search criteria. A search of the literature was conducted up to February 2002. Nevertheless, some trials published later were included (most notably the DART-2 study). Accordingly, how the studies were selected is not clear.
Combining outcomes from studies conducted in different populations. In two endpoint studies, EPA and DHA reduced total mortality mainly by reducing sudden cardiac death, but not non-fatal myocardial infarctions 4,8 . These trials were conducted in Europe , an area with a high incidence of sudden cardiac death. However, in populations with a high background intake of marine omega-3 fatty acids, like the Japanese, sudden cardiac death rarely occurs, and increasing intake of EPA reduced the occurrence of other major cardiovascular events, like fatal and non-fatal myocardial infarctions. Therefore, uncritically combining endpoints across vastly different cultures is not scientifically sound.
 Inconsistencies in logic. It is stated with respect to DART-2, that “this RCT had the longest follow-up of all RCTs and the harmful effects of methylmercury could be cumulative.” This is a puzzling statement for two reasons: 1) there is no conclusive evidence that the amount of methylmercury obtained from 2 oily fish meals per week increases risk for cardiovascular disease, and 2) the excess mortality was seen, not in the fish advice group where methylmercury might conceivably have played a role, but in the group taking fish oil capsules which are free of methylmercury.  The authors then go on to state “This advice [i.e. to eat more oily fish especially after myocardial infarction] should continue at present.” If methylmercury was the problem, then advice to eat fish should not continue at present. 
Attempting to treat diets/supplements as drugs. Truswell has recently published a critique of the Cochrane approach to meta-analysis, noting that their approach, which works reasonably well for drug studies, is not appropriate for dietary interventions 9 . He notes that no expert committees or international bodies have embraced past Cochrane conclusions regarding the role of nutritional interventions in CHD.
         A number of studies using different scientific methodologies have appeared since the cut-off date of the Cochrane analysis (2002 or 2003). They continue to show a protective effect of EPA and DHA for cardiovascular endpoints 10,11 . One example is the randomized open-label Japan EPA Lipid Intervention Study (JELIS), conducted in Japan in 18,645 hyperlipidemic persons being treated with statins who were followed for 4.6 years 12 . This study (reported at the AHA meeting in 2005) found a 19% reduction in major adverse cardiovascular events in the EPA group (p=0.01). 
        The weight of the evidence in favour of omega-3 fatty acids does not rest solely on the publications chosen for the Cochrane analysis as alluded to above. Each type of scientific evidence has its inherent limitations, and therefore, conclusions must be drawn based upon the magnitude of the effect and consistency of the results seen using all types of research paradigms – clinical trials, observational studies, and mechanistic experimental investigations 13,14 . Taking the weight of the scientific evidence together, the cardiovascular benefit of fish and fish oils has clearly been demonstrated. 
        In our view, the weight of the evidence available in May of 2006 is sufficient to conclude, even in light of the Cochrane analysis, that EPA and DHA reduce risk for cardiovascular diseases. Not only do we feel so, but also the American Heart Association/American College of Cardiology 15 , the European Society for Cardiology 16 , a systematic review conducted for the Agency for Healthcare Research and Quality at the NIH 17 , the Harvard Center for Risk Analysis 18 , and a number of other national and international bodies 19-22 .
Taken together,  we see no reason why ISSFAL should  revise its previous (2004) statement on omega-3 fatty acids and cardiovascular disease in light of the Cochrane analysis.

Clemens von Schacky, Medizinische Klinik und Poliklinik Innenstadt, University of Munich, Munich, Germany
William S Harris, South Dakota Health Research Foundation, University of South Dakota,Sioux Falls , South Dakota ,USA
Dariush Mozaffarian, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School ,Boston ,MA,USA 
Penny M. Kris-Etherton, Department of Nutritional Sciences, The Pennsylvania State University, University Park,Pennsylvania,USA

Correspondence to: C. von Schacky, Medizinische Klinik und Poliklinik Innenstadt, University of Munich, Ziemssenstr. 1, D-80336 Munich, Germany. e-mail: Clemens.vonschacky@med.uni-muenchen.de

Reference List: 
 Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ, Worthington HV, Durrington PN, Higgins JP, Capps NE, Riemersma RA, Ebrahim SB, Smith GD. Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review. BMJ. 2006;332:752-760.
    Burr ML, Ashfield-Watt PA, Dunstan FD, Fehily AM, Breay P, Ashton T, Zotos PC, Haboubi NA, Elwood PC. Lack of benefit of dietary advice to men with angina: results of a controlled trial. Eur J Clin Nutr. 2003;57:193-200.
   Bucher HC, Hengstler P, Schindler C, Meier G. N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials. Am J Med. 2002;112:298-304.
   Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, Elwood PC, Deadman NM. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989;2:757-761.
Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-1278.
   Tavazzi L, Tognoni G, Franzosi MG, Latini R, Maggioni AP, Marchioli R, Nicolosi GL, Porcu M. Rationale and design of the GISSI heart failure trial: a large trial to assess the effects of n-3 polyunsaturated fatty acids and rosuvastatin in symptomatic congestive heart failure. Eur J Heart Fail. 2004;6:635-641.
   White C. Suspected research fraud: difficulties of getting at the truth. BMJ. 2005;331:281-288.
Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio R, Franzosi MG, Geraci E, Levantesi G, Maggioni AP, Mantini L, Marfisi RM,             Mastrogiuseppe G,      Mininni N, Nicolosi GL, Santini M, Schweiger C, Tavazzi L, Tognoni G, Tucci C, Valagussa F. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002;105:1897-1903.
 Truswell AS. Some problems with Cochrane reviews of diet and chronic disease. Eur J Clin Nutr. 2005;59 Suppl 1:S150-4; discussion S195-6.:S150-S154.
Iso H, Kobayashi M, Ishihara J, Sasaki S, Okada K, Kita Y, Kokubo Y, Tsugane S. Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I. Circulation. 2006;113:195-202.
Calo L, Bianconi L, Colivicchi F, Lamberti F, Loricchio ML, de Ruvo E, Meo A, Pandozi C, Staibano M, Santini M. N-3 Fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial. J Am Coll Cardiol. 2005;45:1723-1728.
 Yokoyama M, Origasa H. Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS). Am Heart J. 2003;146:613-620.
De Caterina R, Zampolli A, Del Turco S, Madonna R, Massaro M. Nutritional mechanisms that influence cardiovascular disease. Am J Clin Nutr. 2006;83:421S-426S.
Harris WS. Extending the cardiovascular benefits of omega-3 Fatty acids. Curr Atheroscler Rep. 2005;7:375-380.
Smith SC, Jr., Allen J, Blair SN, Bonow RO, Brass LM, Fonarow GC, Grundy SM, Hiratzka L, Jones D, Krumholz HM, Mosca L, Pasternak RC, Pearson T, Pfeffer MA, Taubert KA. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113:2363-2372.
 Priori SG, Aliot E, Blomstrom-Lundqvist C, Bossaert L, Breithardt G, Brugada P, Camm JA, Cappato R, Cobbe SM, Di Mario C, Maron BJ, McKenna WJ, Pedersen AK, Ravens U, Schwartz PJ, Trusz-Gluza M, Vardas P, Wellens HJ, Zipes DP. Update of the guidelines on sudden cardiac death of the European Society of Cardiology. Eur Heart J. 2003;24:13-15.
   17.   Wang C, Chung M, Lichtenstein AH, Balk E, Kupelnick B, DeVine D, Lawrence A, Lau J. Effects of omega-3 fatty acids on cardiovascular disease. No. 04-E009-2 (Prepared by the Tufts-New England Medical Center Evidence-based Practice Center, under contract No. 290-02-0022), 1-122. 2004. Rockville, MD, Agency for Healthcare Research and Quality. Evidence Report/Technology Assessment.                                                                                                                                                    
   18.  Konig A, Bouzan C, Cohen JT, Connor WE, Kris-Etherton PM, Gray GM, Lawrence RS, Savitz DA, Teutsch SM. A quantitative analysis of fish consumption and coronary heart disease mortality. Am J Prev Med. 2005;29:335-346.  
 19.  De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, Ebrahim S, Faergeman O, Graham I, Mancia G, Manger C, V, Orth-Gomer K, Perk J, Pyorala K, Rodicio JL, Sans S, Sansoy V, Sechtem U, Silber S, Thomsen T, Wood D. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J. 2003;24:1601-1610.
   20. http://www.issfal.org.uk/Welcome/PolicyStatement3.asp
   21.  http://www.sacn.gov.uk/reports/
  22.  Joint WHO/FAO Expert Consultation. Diet, Nutrition and the Prevention of Chronic Diseases. 916, 89-90. 2003. Geneva, WHO. WHO Technical Report Series.
 The Executive Committee of ISSFAL extends its deep appreciation to the panel  members for the time and effort involved in producing this statement.
June 2006